Packaged antimicrobial medical device and method of preparing same

ABSTRACT

A method of making a packaged antimicrobial suture. The method includes the steps of providing a containment compartment molded from a polymeric resin comprising a polymeric material and an antimicrobial agent, positioning a suture within the containment compartment, the suture comprising one or more surfaces; covering the containment compartment having the suture in an outer package cover having an inner surface, and subjecting the outer package, the containment compartment and the suture to time, temperature and pressure conditions sufficient to vapor transfer an effective amount of the antimicrobial agent from the containment compartment to the suture, while retaining an effective amount of the antimicrobial agent on the containment compartment, thereby substantially inhibiting bacterial colonization on the suture and the containment compartment. A packaged antimicrobial suture is also provided.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 11/301,365,filed on Dec. 13, 2005, and U.S. Ser. No. 11/301,364, filed on Dec. 13,2005, each of which is a continuation-in-part of U.S. Ser. No.10/808,669, filed on Mar. 25, 2004, which is a continuation-in-part ofU.S. Ser. No. 10/603,317 filed on Jun. 25, 2003, which is acontinuation-in-part of U.S. Ser. No. 10/367,497 filed on Feb. 15, 2003,which claimed the benefit of U.S. Provisional Application No. 60/416,114filed on Oct. 4, 2002, the contents of each are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a packaged antimicrobial medical deviceand its methods of making.

BACKGROUND OF THE INVENTION

Each year, patients undergo a vast number of surgical procedures in theUnited States. Current data shows about twenty-seven million proceduresare performed per year. Post-operative or surgical site infections(“SSIs”) occur in approximately two to three percent of all cases. Thisamounts to more than 675,000 SSIs each year.

The occurrence of SSIs is often associated with bacteria that cancolonize on implantable medical devices used in surgery. During asurgical procedure, bacteria from the surrounding atmosphere may enterthe surgical site and attach to the medical device. Specifically,bacteria can spread by using the implanted medical device as a pathwayto surrounding tissue. Such bacterial colonization on the medical devicemay lead to infection and trauma to the patient. Accordingly, SSTs maysignificantly increase the cost of treatment to patients.

Implantable medical devices that contain antimicrobial agents applied toor incorporated within have been disclosed and/or exemplified in theart. Examples of such devices are disclosed in European PatentApplication No. EP 0 761 243. Actual devices exemplified in theapplication include French Percuflex catheters. The catheters weredip-coated in a coating bath containing2,4,4′-tricloro-2-hydroxydiphenyl ether (Ciba Geigy Irgasan (DP300)) andother additives. The catheters then were sterilized with ethylene oxideand stored for thirty days. Catheters coated with such solutionsexhibited antimicrobial properties, i.e., they produced a zone ofinhibition when placed in a growth medium and challenged withmicroorganism, for thirty days after being coated. It is not apparentfrom the application at what temperature the sterilized, coatedcatheters were stored.

Most implantable medical devices are manufactured, sterilized andcontained in packages until opened for use in a surgical procedure.During surgery, the opened package containing the medical device,packaging components contained therein, and the medical device, areexposed to the operating room atmosphere, where bacteria from the airmay be introduced. Incorporating antimicrobial properties into thepackage and/or the packaging components contained therein substantiallyprevents bacterial colonization on the package and components once thepackage has been opened. The antimicrobial package and/or packagingcomponents in combination with the incorporation of antimicrobialproperties onto the medical device itself would substantially ensure anantimicrobial environment about the sterilized medical device.

SUMMARY OF THE INVENTION

The present invention relates to packaged antimicrobial medical devicesand methods for preparing such packaged medical devices. In accordancewith embodiments of the present invention, a containment compartment isformed from a polymeric resin comprising a polymeric material and anantimicrobial agent. A medical device is positioned within thecontainment compartment and covered with an outer package cover. Uponsubjecting the medical device so packaged to sufficient conditions, aportion of the antimicrobial agent transfers from the containmentcompartment to the medical device. The transfer of the antimicrobialagent is in an amount sufficient to inhibit bacterial growth on andabout the medical device, the inner surface of the outer package coverand the containment compartment.

In one embodiment, an effective amount of the antimicrobial agent istransferred from the containment compartment to the medical device andthe inner surface of the outer package cover during an ethylene oxidesterilization process.

In another embodiment, the medical device may be substantially free ofantimicrobial agent.

In yet another embodiment, the medical device may be coated with anantimicrobial agent.

In still yet another embodiment, the medical device so packaged issubjected to conditions sufficient to vapor transfer an effective amountof the antimicrobial agent by a process that includes the steps ofplacing the outer package cover, the containment compartment, and themedical device in a sterilization unit; heating the sterilization unitto a first temperature; adjusting the pressure in the sterilization unitto a first pressure value; injecting steam into the sterilization unitto expose the outer package cover, the containment compartment and themedical device to water vapor for a first period of time; adjusting thepressure within the sterilization unit to a second pressure value;introducing a chemical sterilization agent into the sterilization unit;maintaining the chemical sterilization agent in the sterilization unitfor a second period of time to render a sufficient amount ofmicroorganisms within the outer package cover non-viable; removingresidual moisture and chemical sterilization agent from the medicaldevice; and drying the packaged medical device to a desired moisturelevel.

In a further embodiment, the containment compartment may be molded froma polymeric resin that includes a polymeric material and anantimicrobial agent, the antimicrobial agent further including at leastone active agent selected from the group consisting of a biocide, adisinfectant, an antiseptic, an antibiotic, an antimicrobial peptide, alytic bacteriophage, a surfactant; an adhesion blocker; anoligonucleotide, an efflux pump inhibitors; a photosensitive dye, animmune modulator and a chelator.

In still further embodiment, the containment compartment is molded byinjection molding.

The present invention is also directed to a method for preparing apackaged antimicrobial medical device, which includes the steps ofproviding a containment compartment molded from a polymeric resincomprising a polymeric material and an antimicrobial agent; positioninga medical device within the containment compartment, the medical devicecomprising one or more surfaces; covering the containment compartmenthaving the medical device in an outer package cover having an innersurface; and subjecting the outer package cover, the containmentcompartment and the medical device to time, temperature and pressureconditions sufficient to vapor transfer an effective amount of theantimicrobial agent from the containment compartment to the medicaldevice, while retaining an effective amount of the antimicrobial agenton the containment compartment, thereby substantially inhibitingbacterial colonization on the medical device and the containmentcompartment.

The present invention also relates to packaged antimicrobial sutures andmethods for preparing such packaged sutures. In accordance therewith, acontainment compartment is formed from a polymeric resin comprising apolymeric material and an antimicrobial agent. A suture is positionedwithin the containment compartment and covered with an outer packagecover. Upon subjecting the suture so packaged to sufficient conditions,a portion of the antimicrobial agent transfers from the containmentcompartment to the suture. The transfer of the antimicrobial agent is inan amount sufficient to inhibit bacterial growth on and about thesuture, the inner surface of the outer package cover and the containmentcompartment.

The present invention is also directed to a method for preparing apackaged antimicrobial suture. The method includes the steps ofproviding a containment compartment molded from a polymeric resincomprising a polymeric material and an antimicrobial agent; positioninga suture within the containment compartment, the suture comprising oneor more surfaces; covering the containment compartment having the suturein an outer package cover having an inner surface; and subjecting theouter package cover, the containment compartment and the suture to time,temperature and pressure conditions sufficient to vapor transfer aneffective amount of the antimicrobial agent from the containmentcompartment to the suture, while retaining an effective amount of theantimicrobial agent on the containment compartment, therebysubstantially inhibiting bacterial colonization on the suture and thecontainment compartment.

In one embodiment, an effective amount of the antimicrobial agent istransferred from the containment compartment to the suture and the innersurface of the outer package cover during an ethylene oxidesterilization process.

In another embodiment, the suture may be substantially free ofantimicrobial agent.

In yet another embodiment, the suture may be coated with anantimicrobial agent.

In still yet another embodiment, the suture so packaged is subjected toconditions sufficient to vapor transfer an effective amount of theantimicrobial agent by a process that includes the steps of covering theouter package cover and the suture in a sterilization unit; heating thesterilization unit to a first temperature; adjusting the pressure in thesterilization unit to a first pressure value; injecting steam into thesterilization unit to expose the outer package cover, the containmentcompartment and the suture to water vapor for a first period of time;adjusting the pressure within the sterilization unit to a secondpressure value; introducing a chemical sterilization agent into thesterilization unit; maintaining the chemical sterilization agent in thesterilization unit for a second period of time to render a sufficientamount of microorganisms on the inner surface of the outer package covernon-viable; removing residual moisture and chemical sterilization agentfrom the suture; and drying the packaged suture to a desired moisturelevel.

In a further embodiment, the containment compartment may be molded froma polymeric resin that includes a polymeric material and anantimicrobial agent, the antimicrobial agent further including at leastone active agent selected from the group consisting of a biocide, adisinfectant, an antiseptic, an antibiotic, an antimicrobial peptide, alytic bacteriophage, a surfactant; an adhesion blocker; anoligonucleotide, an efflux pump inhibitors; a photosensitive dye, animmune modulator and a chelator.

In still further embodiment, the containment compartment is molded byinjection molding.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further explained in the description that follows withreference to the drawings illustrating, by way of non-limiting examples,various embodiments of the invention wherein:

FIG. 1 is a top plan view of a packaged antimicrobial medical device ofthe type disclosed herein, wherein the medical device is a single needleand suture.

FIG. 2 is a photographic representation showing the uniformity ofdistribution by zone of inhibition method from containment compartmentto after the sterilization process.

FIG. 3 presents zone of inhibition data versus time for a suturepackaged in accordance herewith.

FIG. 4 presents parts-per-million triclosan values versus time for asuture packaged in accordance herewith.

FIG. 5 presents zone of inhibition data versus time for a suturepackaged in accordance herewith.

FIG. 6 presents parts-per-million triclosan values versus time for asuture packaged in accordance herewith.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Reference is now made to FIGS. 1-6 wherein like numerals are used todesignate like elements throughout.

Packaged Antimicrobial Medical Device

Referring now to FIG. 1, one embodiment of the packaged antimicrobialmedical device 10 includes a containment compartment 12 molded from apolymeric resin comprising a polymeric material and an antimicrobialagent. A medical device 14, which may be a needle 16 and suture 18having one or more surfaces 20 is positioned within the containmentcompartment 12. The medical device 14 may be initially substantiallyfree of antimicrobial agent or, in another embodiment, may be coatedwith an antimicrobial agent. An outer package cover 22 may be employed,the outer package cover 22 having an inner surface 24 for placing thecontainment compartment having said medical device therein.

The containment compartment 12 of packaged antimicrobial medical device10 includes a base member 26 and a channel cover member 28. Base member26 includes a top side, bottom side, and an outer periphery 30. Asshown, an outer package cover 22 may be positioned upon channel covermember 28 and within outer periphery 30, to fully enclose medical device14. The base member 26 may be a substantially flat substantially ovalshaped member having a longitudinal axis. While in the case of packagedsutures, it may be desired that the base member 26 of packagedantimicrobial medical device 10 be oval shaped, other configurations canbe used including circular, polygonal, square with rounded corners, andthe like and combinations thereof and equivalents thereof. Channel cover28 includes a top side, bottom side, periphery 32 and longitudinal axis.

The packaged antimicrobial medical device 10 of the present inventionmay be assembled in the following manner. Base member 26 is aligned withchannel cover member 28 so that rivets, if employed are in alignmentwith the rivet receiving holes, and locating pins, if employed, are inalignment with corresponding openings. Also, winding pin openings, ifemployed, are aligned with corresponding openings. Then, channel covermember 28 is then mounted to base member 26 such that rivets, ifemployed, are inserted into and through corresponding holes and locatingpins, if employed are inserted through corresponding holes 130. The endsof the rivets, if employed, may be spread by using conventionaltechniques such as heating, ultrasonic treatments, and the like so thatthe channel cover member 28 is firmly affixed to the base member 26. Inthis embodiment, when containment compartment 12 is so formed, a channel34 is formed, which may advantageously house a wound suture 18.

Further details regarding the construction and geometry of thecontainment compartments and packages formed therefrom are more fullydescribed in U.S. Pat. Nos. 6,047,815; 6,135,272 and 6,915,623, thecontents of each are hereby incorporated by reference in their entiretyfor all that they disclose.

Containment compartment 12 of the present invention may be manufacturedfrom conventional moldable materials. It is especially preferred to usepolyolefin materials such as polyethylene and polypropylene, otherthermoplastic materials, and polyester materials such as nylon, andequivalents thereof. Preferably the containment compartments 12 of thepresent invention may be injection molded, however, they may be formedby other conventional processes and equivalents thereof includingthermo-forming. If desired, the packages may be manufactured asindividual assemblies or components which are then assembled.

The sutures and needles that can be packaged in the packages 10 of thepresent invention include conventional surgical needles and conventionalbioabsorbable and nonabsorbable surgical sutures and equivalentsthereof. The packages of the present invention are useful to packagesmall diameter sutures which were previously difficult to package intray packages because of removal or hang-up problems upon withdrawal ofsuch suture from the packages. These problems have been overcome usingthe packages of the present invention.

The polymeric material for use in forming the resin for use in themolding of the containment compartment 12 may be selected fromconventional thermoplastic materials, such as polyethylene andpolypropylene, from polyesters, such as polyvinyl chloride,polypropylene, polystyrene, polyethylene, polyesters, includingpoly(ethylene terephthalate) (PET), nylon, and equivalents and blendsthereof. In one embodiment, high density polyethylene (HDPE) may beemployed as the polymeric material. The packages 10 of the presentinvention may be injection molded, however, the containment compartments12 may be formed by other conventional processes and equivalents thereofincluding thermoforming.

As indicated above, the polymeric resin used to mold containmentcompartment 12 also includes an antimicrobial agent. Suitableantimicrobial agents may be selected from, but are not limited to,halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinationsthereof. In particular, the antimicrobial agent may be a halogenated2-hydroxy diphenyl ether and/or a halogenated 2-acyloxy diphenyl ether,as described in U.S. Pat. No. 3,629,477, and represented by thefollowing formula:

In the above formula, each Hal represents identical or different halogenatoms, Z represents hydrogen or an acyl group, and w represents apositive whole number ranging from 1 to 5, and each of the benzenerings, but preferably ring A can also contain one or several lower alkylgroups which may be halogenated, a lower alkoxy group, the allyl group,the cyano group, the amino group, or lower alkanoyl group. Preferably,methyl or methoxy groups are among the useful lower alkyl and loweralkoxy groups, respectively, as substituents in the benzene rings. Ahalogenated lower alkyl group, trifluoromethyl group is preferred.

Antimicrobial activity similar to that of the halogen-o-hydroxy-diphenylethers of the above formula is also attained using the O-acylderivatives thereof which partially or completely hydrolyze under theconditions for use in practice. The esters of acetic acid, chloroaceticacid, methyl or dimethyl carbamic acid, benzoic acid, chlorobenzoicacid, methylsulfonic acid and chloromethylsulfonic acid are particularlysuitable.

One particularly preferred antimicrobial agent within the scope of theabove formula is 2,4,4′-trichloro-2′-hydroxydiphenyl ether, commonlyreferred to as triclosan (manufactured by Ciba Geigy under the tradename Irgasan DP300 or Irgacare MP). Triclosan is a white powdered solidwith a slight aromatic/phenolic odor. As may be appreciated, it is achlorinated aromatic compound which has functional groups representativeof both ethers and phenols. Triclosan is only slightly soluble in water,but soluble in ethanol, diethyl ether, and stronger basic solutions suchas 1 M sodium hydroxide. Triclosan can be made from the partialoxidation of benzene or benzoic acid, by the cumene process, or by theRaschig process. It can also be found as a product of coal oxidation

Triclosan is a broad-spectrum antimicrobial agent that has been used ina variety of products, and is effective against a number of organismscommonly associated with SSIs. Such microorganisms include, but are notlimited to, genus Staphylococcus, Staphylococcus epidermidis,Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis,methicillin-resistant Staphylococcus aureus, and combinations thereof.

In addition to the antimicrobial agents described above, the medicaldevice optionally may have a biocide, a disinfectant and/or anantiseptic, including but not limited to alcohols such as ethanol andisopropanol; aldehydes such as glutaraldehyde and formaldehyde; anilidessuch as triclorocarbanilide; biguanides such as chlorhexidine;chlorine-releasing agents such as sodium hypochlorite, chlorine dioxideand acidified sodium chlorite; iodine-releasing agents such aspovidone-iodine and poloxamer-iodine; metals such as silver nitrate,silver sulfadiazine, other silver agents, copper-8-quinolate and bismuththiols; peroxygen compounds such as hydrogen peroxide and peraceticacid; phenols; quaternary ammonium compounds such as benzalkoniumchloride, cetrimide and ionenes-polyquaternary ammonium compounds. Themedical device optionally may have antibiotics, including but notlimited to penicillins such as amoxicillin, oxacillin and piperacillin;cephalosporins parenteral such as cefazolin, cefadroxil, cefoxitin,cefprozil, cefotaxime and cefdinir; monobactams such as aztreonam;beta-lactamase inhibitors such as clavulanic acid sulbactam;glycopeptide such as vancomycin; polymixin; quinolones such as nalidixicacid, ciprofloxacin and levaquin; metranidazole; novobiocin;actinomycin; rifampin; aminoglycosides such as neomycin and gentamicin;tetracyclines such as doxycycline; chloramphenicol; macrolide such aserythromycin; clindamycin; sulfonamide such as sulfadiazine;trimethoprim; topical antibiotics; bacitracin; gramicidin; mupirocin;and/or fusidic acid. Optionally, the medical device may haveantimicrobial peptides such as defensins, magainin and nisin; lyticbacteriophage; surfactants; adhesion blockers such as antibodies,oligosaccharides and glycolipids; oligonucleotides such as antisenseRNA; efflux pump inhibitors; photosensitive dyes such as porphyrins;immune modulators such as growth factors, interleukins, interferons andsynthetic antigens; and/or chelators such as EDTA, sodiumhexametaphosphate, lactoferrin and transferrin.

To form the polymeric resin used to mold containment compartment 12,pellets of an antibacterial agent, such as triclosan, 4% by weight, maybe mechanically mixed with pellets of a titanium dioxide colorantmixture, 3% by weight, and pellets of a standard mold release agent,such as ampacent, 3% by weight. The mixture so formed may be extrudedusing conventional equipment to form a colorant mixture. The extrudedtriclosan/colorant/mold-release agent mixture may then be compoundedwith a high density polyethylene (HDPE) polymer to form the resin to beused in manufacturing containment compartments, such as suture holdingtrays. The resultant polymer resin can then be injection molded to formtwo-component containment compartments 12.

One embodiment of the packaged antimicrobial medical device includes acontainment compartment for securing the medical device that resideswithin, the containment compartment molded from a polymeric resincomprising a polymeric material and an antimicrobial agent. A medicaldevice comprising one or more surfaces is positioned within thecontainment compartment. An outer package cover having an inner surfacemay be employed to cover the containment compartment and suture.

In one embodiment, the medical device positioned within the containmentcompartment may be initially substantially free of antimicrobial agent.By “initially substantially free” is meant that the medical device sopositioned within the containment compartment has not been treated orcoated with an agent having efficacy as an antimicrobial agent prior topositioning within the containment compartment. In another embodiment,the medical device positioned within the containment compartment may becoated with an antimicrobial agent. By “coated with an antimicrobialagent” is meant that the medical device so positioned within thecontainment compartment has been treated or coated with an agent havingefficacy as an antimicrobial agent prior to positioning within thecontainment compartment.

As will be discussed in more detail below, prior to use, the packagedantimicrobial medical device, which includes the outer package cover,containment compartment and medical device may be subjected to time,temperature and pressure conditions sufficient to vapor transfer aneffective amount of antimicrobial agent from the containment compartmentto the medical device and the inner surface of the outer package cover,while retaining an effective amount of said antimicrobial agent on thecontainment compartment, thereby substantially inhibiting bacterialcolonization on the medical device and the containment compartment. Thisvapor transfer mechanism can also increase the antimicrobial efficacyfor medical devices that have been treated or coated with an agenthaving efficacy as an antimicrobial agent prior to positioning withinthe containment compartment when the container compartment has beenformed using the resins described herein. In one embodiment, theeffective amount of said antimicrobial agent transferred from thecontainment compartment to the medical device and the inner surface ofthe outer package cover is transferred during an ethylene oxidesterilization process.

In another embodiment, the packaged medical device includes acontainment compartment molded from a polymeric resin comprising apolymeric material and an antimicrobial agent; a suture comprising oneor more surfaces and positioned within the containment compartment; andan outer package cover having an inner surface for covering thecontainment compartment having the suture therein. In one embodiment,the suture positioned within the containment compartment issubstantially free of antimicrobial agent. In another embodiment, thesuture positioned within the containment compartment is coated with anantimicrobial agent. In still another embodiment, the antimicrobialagent is selected from the group consisting of halogenated hydroxylethers, acyloxydiphenyl ethers, and combinations thereof.

As with the packaged medical device disclosed herein, prior to use, thepackaged antimicrobial suture, which includes the outer package cover,containment compartment and suture may be subjected to time, temperatureand pressure conditions sufficient to vapor transfer an effective amountof antimicrobial agent from the containment compartment to the sutureand the inner surface of the outer package cover, while retaining aneffective amount of said antimicrobial agent on the containmentcompartment, thereby substantially inhibiting bacterial colonization onthe suture and the containment compartment. This vapor transfermechanism can also increase the antimicrobial efficacy for sutures thathave been treated or coated with an agent having efficacy as anantimicrobial agent prior to positioning within the containmentcompartment when the container compartment has been formed using theresins described herein. In one embodiment, the effective amount of saidantimicrobial agent transferred from the containment compartment to themedical device and the inner surface of the outer package cover istransferred during an ethylene oxide sterilization process.

The medical devices described herein are generally implantable medicaldevices, including but not limited to mono and multifilament sutures,surgical meshes such as hernia repair mesh, hernia plugs, brachy seedspacers, suture clips, suture anchors, adhesion prevention meshes andfilms, and suture knot clips. Also included are implantable medicaldevices that are absorbable and non-absorbable. An absorbable polymer isdefined as a polymer that, when exposed to physiological conditions,will degrade and be absorbed by the body over a period of time.Absorbable medical devices typically are formed from generally known,conventional absorbable polymers including, but not limited to,glycolide, lactide, co-polymers of glycolide, or mixtures of polymers,such as polydioxanone, polycaprolactone and equivalents thereof.Preferably, the polymers include polymeric materials selected from thegroup consisting of greater than about 70% polymerized glycolide,greater than about 70% polymerized lactide, polymerized1,4-dioxan-2-one, greater than about 70% polypeptide, copolymers ofglycolide and lactide, greater than about 70% cellulosics and cellulosicderivatives. Examples of absorbable medical device include mono andmultifilament sutures. The multifilament suture includes sutures whereina plurality of filaments is formed into a braided structure. Examples ofnon-absorbable medical devices include mono and multifilament sutures,surgical meshes such as hernia repair mesh, hernia plugs and brachy seedspacers, which may be polymeric or nonpolymeric.

For embodiments of the present invention that contemplate the use of amedical device that will be treated or coated with an agent havingefficacy as an antimicrobial agent prior to packaging, it isadvantageous to use a coating composition as a vehicle for deliveringthe antimicrobial agent to the surface of the device where such coatingalready is used conventionally in the manufacture of the device, suchas, for example, absorbable and non-absorbable multifilament sutures.Examples of medical devices, as well as coatings that may be appliedthereto, may be found in U.S. Pat. Nos. 4,201,216; 4,027,676; 4,105,034;4,126,221; 4,185,637; 3,839,297; 6,260,699; 5,230,424; 5,555,976;5,868,244; and 5,972,008; each of which is hereby incorporated herein inits entirety. As disclosed in U.S. Pat. No. 4,201,216, the coatingcomposition may include a film-forming polymer and a substantiallywater-insoluble salt of a C₆ or higher fatty acid. As another example,an absorbable coating composition that may be used for an absorbablemedical device may include poly(alkylene oxylates) wherein the alkylenemoieties are derived from C₆ or mixtures of C₄ to C₁₂ diols, which isapplied to a medical device from a solvent solution, as disclosed inU.S. Pat. No. 4,105,034. The coating compositions of the presentinvention may include a polymer or co-polymer, which may include lactideand glycolide, as a binding agent. The compositions may also includecalcium stearate, as a lubricant, and an antimicrobial agent. Medicaldevices not conventionally employing a coating in the manufacturingprocess, however, also may be coated with a composition comprising anantimicrobial agent. The coating may be applied to the device by, forexample, dip coating, spray coating, suspended drop coating, or anyother conventional coating means.

Absorbable medical devices are moisture sensitive, that is, they aredevices that will degrade if exposed to moisture in the atmosphere or inthe body. It is known by those of ordinary skill in the art that medicaldevices made from absorbable polymers may deteriorate and lose theirstrength if they come into contact with water vapor prior to use duringsurgery. For instance, the desirable property of in vivo tensilestrength retention for sutures will be rapidly lost if the sutures areexposed to moisture for any significant period of time prior to use.Therefore, it is desirable to use a hermetically sealed package forabsorbable medical devices. A hermetically sealed package is definedherein to mean a package made of a material that serves as both asterile barrier and a gas barrier, i.e., prevents or substantiallyinhibits moisture and gas permeation.

Materials useful for constructing the package for absorbable medicaldevices, for example, include single and multilayered conventional metalfoil products, often referred to as heat-sealable foils. These types offoil products are disclosed in U.S. Pat. No. 3,815,315, which is herebyincorporated by reference in its entirety. Another type of foil productthat may be utilized is a foil laminate referred to in the field of artas a peelable foil. Examples of such peelable foil and substrates aredisclosed in U.S. Pat. No. 5,623,810, which is hereby incorporated byreference in its entirety. If desired, conventional non-metallic polymerfilms in addition to or in lieu of metal foil may be used to form thepackage for absorbable medical devices. Such films are polymeric and mayinclude conventional polyolefins, polyesters, acrylics and the like,combinations thereof and laminates. These polymeric films substantiallyinhibit moisture and oxygen permeation and may be coated withconventional coatings, such as, for example, mineral coatings thatdecrease or reduce gas intrusion. The package may comprise a combinationof polymer and metal foils, particularly a multi-layerpolymer/metal-foil composite.

Nonabsorbable medical devices may be packaged in any of the materialsdescribed above. In addition, it is desirable to package nonabsorbablemedical devices in a package made of a material that serves as a sterilebarrier, such as a porous material, i.e., medical grade paper, or apolymeric film that is permeable to moisture and gas, i.e., Tyvek® film,manufactured by DuPont and made from high-density polyethylene fibers.

Packages for surgical needles, sutures and combinations including thesuture and a surgical needle typically comprise a suture tray as thecontainment compartment, for securely holding the suture and/or surgicalneedle in place. Types other than that shown in FIG. 1 are contemplatedherein. These other designs typically include a molded plastic trayhaving a central floor surrounded by an outer winding channel forreceiving and retaining a suture, e.g., an oval channel. The containmentcompartment may further include a medical grade paper or plastic coverthat may be mounted to the top of the winding channel, or the moldedplastic tray may have molded retainer elements, in order to maintain thesuture in the channel. Containment compartments having winding channelsare illustrated in the following, each of which is hereby incorporatedby reference in its entirety: U.S. Pat. Nos. 4,967,902, 5,213,210 and5,230,424.

Microorganisms of the genus Staphylococcus are the most prevalent of allof the organisms associated with device-related surgical site infection.S. aureus and S. epidermidis are commonly present on patients' skin andas such are introduced easily into wounds. One of the most efficaciousantimicrobial agents against Staphylococcus is2,4,4′-trichloro-2′-hydroxydiphenyl ether. This compound has a minimuminhibitory concentration (MIC) against S. aureus of 0.01 ppm, asmeasured in a suitable growth medium and as described by Bhargava, H. etal in the American Journal of Infection Control, June 1996, pages209-218. The MIC for a particular antimicrobial agent and a particularmicroorganism is defined as the minimum concentration of thatantimicrobial agent that must be present in an otherwise suitable growthmedium for that microorganism, in order to render the growth mediumunsuitable for that microorganism, i.e., the minimum concentration toinhibit growth of that microorganism. The phrase “an amount sufficientto substantially inhibit bacterial colonization” as used herein isdefined as the minimum inhibitory concentration for S. aureus orgreater.

A demonstration of this MIC is seen in the disk diffusion method ofsusceptibility. A filter paper disk, or other object, impregnated with aparticular antimicrobial agent is applied to an agar medium that isinoculated with the test organism. Where the anti-microbial agentdiffuses through the medium, and as long as the concentration of theantimicrobial agent is above the minimum inhibitory concentration (MIC),none of the susceptible organism will grow on or around the disk forsome distance. This distance is called a zone of inhibition. Assumingthe antimicrobial agent has a diffusion rate in the medium, the presenceof a zone of inhibition around a disk impregnated with an antimicrobialagent indicates that the organism is inhibited by the presence of theantimicrobial agent in the otherwise satisfactory growth medium. Thediameter of the zone of inhibition is inversely proportional to the MIC.

Alternatively, the concentration of triclosan present on the surface ofa medical device such as a coated suture may be greater than about 0.01ppm (wt./wt. coating) or between about 30 ppm to 5,000 ppm (wt./wt.suture). The concentration of triclosan on the surface of package orcontainment compartment may be between about 5 ppm to 5,000 ppm (wt./wt.package or compartment). For other particular applications, however,higher amounts of antimicrobial agent may be useful and should beconsidered well within the scope of the present invention

Method for Making a Packaged Antimicrobial Medical Device

In accordance with various methods of the present invention, acontainment compartment is provided that has been molded from apolymeric resin comprising a polymeric material and an antimicrobialagent. In one embodiment, a medical device that is initiallysubstantially free of an antimicrobial agent may be provided. Themedical device is positioned within the containment compartment. Thecontainment compartment having the suture is covered with an outerpackage cover having an inner surface. Subsequently, the outer packagecover, the containment compartment and the medical device are subjectedto time, temperature and pressure conditions sufficient to vaportransfer a portion of the antimicrobial agent from the containmentcompartment to the medical device and the inner surface of the outerpackage cover.

The rate of transfer of an antimicrobial agent such as triclosan fromthe containment compartment to the medical device and the inner surfaceof the outer package cover is substantially dependent upon the time,temperature and pressure conditions under which the package with thecontainment compartment and the medical device is processed, stored andhandled. For example, it has been observed that triclosan is capable oftransferring from a suture to a containment compartment (in a closedvial at atmospheric pressure) when the temperature is maintained at 55°C. over a period of time. The conditions to effectively vapor transferan antimicrobial agent such as triclosan include a closed environment,atmospheric pressure, a temperature of greater than 40° C., for a periodof time ranging from 4 to 8 hours. Also included are any combinations ofpressure and temperature to render a partial pressure for theantimicrobial agent that is the same as the partial pressure renderedunder the conditions described above, in combination with a period oftime sufficient to render an effective amount or concentration of theantimicrobial agent on the containment compartment, medical device andthe inner surface of the outer package cover, i.e., the minimuminhibitory concentration (MIC) or greater. Specifically, it is known toone of ordinary skill that if the pressure is reduced, the temperaturemay be reduced to effect the same partial pressure. Alternatively, ifthe pressure is reduced, and the temperature is held constant, the timerequired to render an effective amount or concentration of theantimicrobial agent on the containment compartment, medical device andthe inner surface of the outer package cover may be shortened. While aportion of the antimicrobial agent is transferred from the containmentcompartment to the medical device and the inner surface of the outerpackage cover during this process, a second portion is retained on thesurface of the containment compartment. Accordingly, after the transfer,the medical device and the package and/or the containment compartmentcontain the antimicrobial agent in an amount effective to substantiallyinhibit bacterial colonization thereon and thereabout.

Medical devices typically are sterilized to render microorganismslocated thereon non-viable. In particular, sterile is understood in thefield of art to mean a minimum sterility assurance level of 10⁻⁶.Examples of sterilization processes are described in U.S. Pat. Nos.3,815,315; 3,068,864; 3,767,362; 5,464,580; 5,128,101; and 5,868,244;each of which is incorporated herein in its entirety. Specifically,absorbable medical devices may be sensitive to radiation and heat.Accordingly, it may be desirable to sterilize such devices usingconventional sterilant gases or agents, such as, for example, ethyleneoxide gas.

An ethylene oxide sterilization process is described below, since thetime, temperature and pressure conditions sufficient to vapor transfer aportion of the antimicrobial agent from the medical device to thepackage and/or containment compartment, are present in an ethylene oxidesterilization process. However the time, temperature and pressureconditions sufficient to vapor transfer the antimicrobial agent from themedical device to the package and/or containment compartment may beeffected alone or in other types of sterilization processes, and are notlimited to an ethylene oxide sterilization process or to sterilizationprocesses in general.

As discussed above, absorbable medical devices are sensitive to moistureand are therefore often packaged in hermetically sealed packages, suchas sealed foil packages. However, sealed foil packages are alsoimpervious to sterilant gas. In order to compensate for this and utilizefoil packages in ethylene oxide gas sterilization processes, processeshave been developed using foil packages having gas permeable or perviousvents (e.g., TYVEK® polymer). The gas permeable vents are mounted to anopen end of the package and allow the passage of air, water vapor andethylene oxide into the interior of the package. After the sterilizationprocess is complete, the package is sealed adjacent to the vent, and thevent is cut away or otherwise removed, thereby producing a gasimpervious hermetically sealed package. Another type of foil packagehaving a vent is a pouch-type package having a vent mounted adjacent toan end of the package, wherein the vent is sealed to one side of thepackage creating a vented section. After the sterilization process iscomplete the package is sealed adjacent to the vent, and the package iscut away for the vented section

The medical device may be substantially free of, and preferablycompletely free of, antimicrobial agent prior to the transfer of theantimicrobial agent from the containment compartment to the medicaldevice and the inner surface of the outer package cover. The medicaldevice may first be placed within the containment compartment, ifnecessary, and then within the package. After the peripheral seal andside seals have been formed in the package, the packaged medical devicemay be placed into a conventional ethylene oxide sterilization unit. Ifthe package is a foil package, the gas permeable vents described abovemay be used. Prior to the start of the cycle, the sterilization unit maybe heated to an internal temperature of about 25° C. The sterilizationunit is maintained about 22 to 37° C. throughout the humidification andsterilization cycles. Next, a vacuum may be drawn on the sterilizationunit to achieve a vacuum of approximately 1.8 to 6.0 kPa. In ahumidification cycle, steam then may be injected to provide a source ofwater vapor for the product to be sterilized. The packaged medicaldevices may be exposed to water vapor in the sterilization unit for aperiod of time of about 60 to 90 minutes. Times may vary, however,depending upon the medical device being sterilized.

Following this humidification portion of the cycle, the sterilizationunit may be pressurized by the introduction of dry inert gas, such asnitrogen gas, to a pressure of between about 42 and 48 kPa. Once thedesired pressure is reached, pure ethylene oxide may be introduced intothe sterilization unit until the pressure reaches about 95 kPa. Theethylene oxide may be maintained for a period of time effective tosterilize the packaged medical device. For example, the ethylene oxidemay be maintained in the sterilization unit for about 360 to about 600minutes for surgical sutures. The time required to sterilize othermedical devices may vary depending upon the type of product and thepackaging. The ethylene oxide then may be evacuated from thesterilization unit and the unit may be maintained under vacuum at apressure of approximately 0.07 kPa for approximately 150 to 300 minutesin order to remove residual moisture and ethylene oxide from thesterilized packaged medical devices. The pressure in the sterilizationunit may be returned to atmospheric pressure.

The following stage of the process is a drying cycle. The packagedmedical device may be dried by exposure to dry nitrogen and vacuum overa number of cycles sufficient to effectively remove residual moistureand water vapor from the packaged medical device to a preselected level.During these cycles, the packaged medical device may be subjected to anumber of pressure increases and decreases, at temperatures greater thanroom temperature. Specifically, the jacket temperature of the dryingchamber may be maintained at a temperature of between approximately 53°C. to 57° C. throughout the drying cycle. Higher temperatures, however,may be employed, such as about 65° C. to 70° C. for sutures, and higherdepending upon the medical device being sterilized. A typical dryingcycle includes the steps of increasing the pressure with nitrogen toapproximately 100 kPa, evacuating the chamber to a pressure ofapproximately 0.07 kPa over a period of 180 to 240 minutes,reintroducing nitrogen to a pressure of 100 kPa and circulating thenitrogen for approximately 90 minutes, evacuating the chamber to apressure of approximately 0.01 kPa over a period of approximately 240 to360 minutes and maintaining a pressure of not more than 0.005 kPa for anadditional 4 to 96 hours. At the end of the humidification,sterilization and drying cycles, which takes typically about 24 hours,the vessel is returned to ambient pressure with dry nitrogen gas. Oncedrying to the preselected moisture level is complete, the packagedmedical device may be removed from the drying chamber and stored in ahumidity controlled storage area.

Upon completion of the sterilization process, the antimicrobial medicaldevice, the outer package cover and the containment compartment havethereon an amount of the antimicrobial agent effective to substantiallyinhibit colonization of bacteria on or adjacent the antimicrobialdevice, the package and/or the containment compartment.

Example 1

In preparation for forming a containment compartment of the typedisclosed herein, pellets of the antibacterial agent triclosan, 4% byweight, were mechanically mixed with pellets of a titanium dioxidecolorant mixture, 3% by weight, and pellets of a standard mold releaseagent, (ampacent), 3% by weight. The mixture was extruded to form acolorant mixture. The extruded triclosan/colorant/mold-release agentmixture was then compounded with a high density polyethylene (HDPE)polymer to form the resin to be used in manufacturing containmentcompartments.

The resultant polymer resin was then injection molded to formtwo-component containment compartments for use as suture trays. Asdisclosed herein, one component is a channel cover member and thesecond, a base member. The construction and geometry of the sutureholding trays are as shown in FIG. 1 and similar to those described U.S.Pat. Nos. 6,047,815; 6,135,272; and 6,915,623. The trays prepared asdescribed above weighed 3 grams each and contained approximately 11.2 mgof triclosan. The channel cover members and the base members of eachtray were joined through ultrasonic bonding.

Example 2

The suture package was assembled in the following manner: A 27″ lengthof Vicryl® suture, size 1 and dyed (a braided multifilament suturecomposed of a copolymer made from 90% glycolide and 10% L-lactide, thatis commercially available from Ethicon, Inc.), initially substantiallyfree of an antimicrobial agent, was placed in the base member of thesuture tray and covered with the channel cover member. The suture trayassemblies, each having the suture and the two-component suture traycomprised of HDPE and triclosan, were arranged in separate cavitiescreated in peelable foil packaging material, i.e., ethyl acrylicacid-coated aluminum foil composite, having a Tyvek® gas-permeable ventmounted to an open end of the packaging material to allow the passage ofair, water vapor and ethylene oxide into the interior of the cavitieswithin the packaging material. The suture assemblies were then ethyleneoxide sterilized, which conveniently subjected the suture assemblies totime, temperature and pressure conditions sufficient to vapor transferan effective amount of the antimicrobial agent from the antimicrobialagent source, i.e., the suture tray incorporating triclosan, to thesuture.

Example 3

After the sterilization process was complete, the individual cavitieswere sealed and the gas permeable vent was effectively excluded to formsealed packages each having a suture assembly contained therein.

The sterilized Vicryl® sutures of Example 2 were then subjected to apaired study, that is, the same suture samples were used for both thestability studies, measuring the concentration of triclosan (ppm) in thesuture over time, and the zone of inhibition testing (ZOI). In addition,a Vicryl® suture of Example 2 was subjected to a uniformity study toascertain whether or not triclosan was distributed evenly throughout thelength of suture.

Example 3A Parts Per Million Stability Testing

The suture samples from Example 2 were divided into two groups andplaced in chambers for long term stability studies testing, run at both25 and 50 deg. C. The study measured the amount of triclosan present inthe suture in parts per million, compiling the data over a two-yearperiod. The triclosan had vapor transferred from the suture holding trayto the suture during the sterilization process. The data from this studyis in Table 1.

Example 3B Zone of Inhibition Testing

The data included in the table below was from zone of inhibition testingperformed on the sutures, when challenged with Escherichia coli ATCC8739 grown in Tryptic Soy broth at 37° C. for 24 h. The culture wasdiluted in sterile 0.85% saline to create inocula with concentrations ofapproximately 1,000,000 cfu (colony forming units) per milliliter. Forthe test, the sutures that had been subjected to the stability testdescribed in Example 3A were aseptically cut into 5-cm pieces. Thepieces were placed in separate sterile Petri dishes with 0.1 ml ofinoculum. Tryptic Soy agar was poured into the plates, and the plateswere incubated at 37° C. for 48 h. Zones of inhibition were read as thedistance in millimeters from the suture to the edge of visible growth.See Table 1.

TABLE 1 Paired Studies of Size 1 Dyed Vicryl ® Suture 11.2 mg 11.2 mg (4wt %) (4 wt %) Time Triclosan Triclosan Temp (days) ZOI (mm) ppm DegreesC. 0 8.7 1322 25 30 11.1 1313 25 90 9.7 1212 25 150 10.3 1276 25 270 8.21344 25 360 9.5 1218 25 940 9.7 1395 25 0 8.7 1322 50 30 9.0 1389 50 9010.6 1484 50 150 10.2 1346 50 360 7.4 1291 50 940 9.7 1476 50

Trays manufactured with 11.2 mg triclosan produced a suture presenting azone of inhibition of 8.7 mm against E. coli at the start of the study.The suture contained 1322 ppm of triclosan at the start of the study and1476 ppm after 940 days. Results of the tests described herein show thatthe use of an antimicrobial agent integrally included in the polymerforming the suture holding tray is an effective means of generating aproduct that exhibits a zone of inhibition when challenged with E. coli.

Example 3C Triclosan Distribution Uniformity Study

The purpose of this study is to determine whether or not the triclosanis evenly distributed in and on the suture, that is, whether or not thetriclosan that had vapor transferred from the suture tray to the suturehas transferred uniformly to the sutures regardless of the position ofthe suture in the tray. FIG. 2 illustrates an empty suture package fromExample 2 used in this study. The sides a, b, c, and d are identified inFIG. 2 and correspond to sides a, b, c, and of FIG. 1.

One package of the Vicryl® suture of Example 2 was opened to reveal thesutures within. A suture length which included one full circumference ofthe tray was cut from the whole. The piece was further cut into fourstrips, one from each of the four quadrants of the package, a, b, c, andd. A zone of inhibition test was conducted on these samples. FIG. 2shows the size of the zone of inhibition for each side, proving that theposition of the suture in the package does not significantly affect thesize of the zone of inhibition. Therefore, the triclosan was depositeduniformly throughout the package.

In an identical manner, trials were run on sutures constructed of sevenmaterials—Coated Vicryl® (polyglactin 910), PDS-II (polydioxanone),Monocryl® Plus (poliglecaprone 25), Ethilon® Nylon, Ethibond Excel®Polyester, Prolene® Polypropylene, and silk, testing 3 sizes of eachsuture—1, 2/0, and 6/0. The amount of triclosan added to the HDPEpolymer included the values in the range from 2 to 9, specifically: 2,4, 6, and 9% by weight of HDPE. The weight percents of triclosanamounted to 5.3, 11.2, 17.1, and 27.1 mg of triclosan per 3 gm trayrespectively, as shown in Table 2.

TABLE 2 Paired Studies of Size 1 Dyed Vicryl ® Suture 5. 11. 17. V27. 5.11. 17. 27. Tem Time mZm mZm mZm mZm mPP mPP mPP mPP C. 0 6. 8. 10. 9.56 132 241 386 2 3 6. 11. 17. 18. 58 131 230 392 2 9 7. 9. 14. 18. 60121 228 386 2 15 8. 10. 11. 15. 55 127 255 409 2 27 5. 8. 62 134 2 36 7.9. 58 121 2 94 7. 9. 13. 19. 57 139 246 397 2 0 6. 8. 10. 9. 56 132 241386 5 3 7. 9. 12. 21. 63 138 252 344 5 9 7. 10. 14. 41. 64 148 240 386 515 8. 10. 13. 41. 62 134 251 365 5 36 6. 7. 67 129 5 94 7. 9. 13. 19. 76147 241 299 5

Trays manufactured with 5.3 mg triclosan produced sutures that presenteda 6.2 mm zone of inhibition at time zero. The suture at time zero had566 ppm of triclosan present. It is clear from the data that as thetriclosan levels increase in the tray, the zone of inhibition and theamount of triclosan present also increase. The level of the zone ofinhibition and the levels of triclosan (ppm) are also affected bystorage conditions. Based on the above data it is possible to achieve aZOI of suitable length and effective levels of triclosan by selectingsuitable parameters.

Example 4 Effect of Time on Efficacy

Suture packages were produced in accordance with Example 2. Additionalsuture packages were also produced in accordance with Example 2, withthe exception that Size 1 Monocryl® Plus sutures were substituted forthe Vicryl® sutures. Periodically, over a 30-month period, the zones ofinhibition was tested for each packaged product type. Additionally,parts per million triclosan values were recorded for each packagedproduct type. These data are presented in FIGS. 3-6 and depict triclosantransfer as a function of time.

All patents, test procedures, and other documents cited herein,including priority documents, are fully incorporated by reference to theextent such disclosure is not inconsistent and for all jurisdictions inwhich such incorporation is permitted.

While the illustrative forms disclosed herein have been described withparticularity, it will be understood that various other modificationswill be apparent to and can be readily made by those skilled in the artwithout departing from the spirit and scope of the disclosure.Accordingly, it is not intended that the scope of the claims appendedhereto be limited to the examples and descriptions set forth herein butrather that the claims be construed as encompassing all the features ofpatentable novelty which reside herein, including all features whichwould be treated as equivalents thereof by those skilled in the art towhich this disclosure pertains.

When numerical lower limits and numerical upper limits are listedherein, ranges from any lower limit to any upper limit are contemplated.

1. A method of making a packaged antimicrobial suture comprising thesteps of: providing a containment compartment molded from a polymericresin comprising a polymeric material and an antimicrobial agent;positioning a suture within the containment compartment, the suturecomprising one or more surfaces; covering the containment compartmenthaving the suture in an outer package cover having an inner surface; andsubjecting the outer package cover, the containment compartment and thesuture to time, temperature and pressure conditions sufficient to vaportransfer an effective amount of the antimicrobial agent from thecontainment compartment to the suture, while retaining an effectiveamount of the antimicrobial agent on the containment compartment,thereby substantially inhibiting bacterial colonization on the sutureand the containment compartment.
 2. The method of making a packagedantimicrobial suture according to claim 1, wherein the suture positionedwithin the containment compartment is substantially free ofantimicrobial agent.
 3. The method of making a packaged antimicrobialsuture according to claim 1, wherein the suture positioned within thecontainment compartment is coated with antimicrobial agent.
 4. Themethod of making a packaged antimicrobial suture according to claim 1,wherein the antimicrobial agent is selected from the group consisting ofhalogenated hydroxyl ethers, acyloxydiphenyl ethers, and combinationsthereof.
 5. The method of making a packaged antimicrobial sutureaccording to claim 1, wherein the effective amount of the antimicrobialagent transferred from the containment compartment to the suture and theinner surface of the outer package cover is transferred during anethylene oxide sterilization process.
 6. The method of making a packagedantimicrobial suture according to claim 1, wherein the step ofsubjecting the outer package cover, the containment compartment and thesuture to conditions sufficient to vapor transfer an effective amount ofthe antimicrobial agent comprises the steps of: placing the outerpackage cover having the containment compartment and the suture thereinin a sterilization unit; heating the sterilization unit to a firsttemperature; adjusting the pressure in the sterilization unit to a firstpressure value; injecting steam into the sterilization unit to exposethe outer package cover, the containment compartment and the suture towater vapor for a first period of time; adjusting the pressure withinthe sterilization unit to a second pressure value; introducing achemical sterilization agent into the sterilization unit; maintainingthe chemical sterilization agent in the sterilization unit for a secondperiod of time to render a sufficient amount of microorganisms on theinner surface of the outer package cover non-viable; removing residualmoisture and chemical sterilization agent from the suture; and dryingthe packaged antimicrobial suture to a desired moisture level.
 7. Themethod of making a packaged antimicrobial suture according to claim 6,wherein the step of introducing a chemical sterilization agent comprisesintroducing ethylene oxide gas into the sterilization unit.
 8. Themethod of claim 1, wherein the containment compartment molded from apolymeric resin comprising a polymeric material and an antimicrobialagent further comprises at least one active agent selected from thegroup consisting of a biocide, a disinfectant, an antiseptic, anantibiotic, an antimicrobial peptide, a lytic bacteriophage, asurfactant; an adhesion blocker; an oligonucleotide, an efflux pumpinhibitors; a photosensitive dye, an immune modulator and a chelator. 9.The method of making a packaged antimicrobial suture according to claim1, wherein the step of subjecting the outer package cover, thecontainment compartment and the suture to time, temperature and pressureconditions sufficient to vapor transfer an effective amount of theantimicrobial agent from the containment compartment to the suture alsotransfers an effective amount of the antimicrobial agent to the innersurface of the outer package cover.
 10. A method of making a packagedmedical device comprising the steps of: providing a containmentcompartment molded from a polymeric resin comprising a polymericmaterial and an antimicrobial agent; positioning a medical device withinthe containment compartment, the medical device comprising one or moresurfaces; covering the containment compartment having the medical devicewith an outer package cover having an inner surface; and subjecting theouter package cover, the containment compartment and the medical deviceto time, temperature and pressure conditions sufficient to vaportransfer an effective amount of the antimicrobial agent from thecontainment compartment to the medical device, while retaining aneffective amount of the antimicrobial agent on the containmentcompartment, thereby substantially inhibiting bacterial colonization onthe medical device and the containment compartment.
 11. The method ofmaking a packaged antimicrobial medical device according to claim 10,wherein the suture positioned within the containment compartment issubstantially free of antimicrobial agent.
 12. The method of making apackaged antimicrobial medical device according to claim 10, wherein thesuture positioned within the containment compartment is coated withantimicrobial agent.
 13. The method of making a packaged antimicrobialmedical device according to claim 10, wherein the antimicrobial agent isselected from the group consisting of halogenated hydroxyl ethers,acyloxydiphenyl ethers, and combinations thereof.
 14. The method ofmaking a packaged medical device according to claim 10, wherein theeffective amount of the antimicrobial agent transferred from thecontainment compartment to the medical device and the inner surface ofthe outer package cover is transferred during an ethylene oxidesterilization process.
 15. A packaged antimicrobial suture comprising: acontainment compartment molded from a polymeric resin comprising apolymeric material and an antimicrobial agent; a suture comprising oneor more surfaces and positioned within said containment compartment; andan outer package cover having an inner surface for covering saidcontainment compartment having said suture therein.
 16. The packagedantimicrobial suture of claim 15, wherein said suture positioned withinsaid containment compartment is substantially free of antimicrobialagent.
 17. The packaged antimicrobial suture of claim 15, wherein saidsuture positioned within said containment compartment is coated withantimicrobial agent.
 18. The packaged antimicrobial suture of claim 15,wherein said antimicrobial agent is selected from said group consistingof halogenated hydroxyl ethers, acyloxydiphenyl ethers, and combinationsthereof.
 19. The packaged antimicrobial suture of claim 15, wherein saidouter package cover, said containment compartment and said suture aresubjected to time, temperature and pressure conditions sufficient tovapor transfer an effective amount of said antimicrobial agent from saidcontainment compartment to said suture and said inner surface of saidouter package cover, while retaining an effective amount of saidantimicrobial agent on said containment compartment, therebysubstantially inhibiting bacterial colonization on said suture and saidcontainment compartment.
 20. A packaged medical device comprising: acontainment compartment molded from a polymeric resin comprising apolymeric material and an antimicrobial agent; a medical devicecomprising one or more surfaces and positioned within said containmentcompartment; and an outer package cover having an inner surface forcovering said containment compartment having said medical devicetherein.